update on eleventh icdra recommendations and who · pdf filepharmacovigilance practices ......

14 TWELFTH INTERNATIONAL CONFERENCE OF DRUG REGULATORY AUTHORITIES

3 April 2006Plenary 2

Reflections on Eleventh ICDRA (PL2-1)

Fernando de Andres, Spanish Agency for Medicines and Medical Devices,Spain

Global Progress Report (PL2-2)

Dr Howard Zucker, World Health Organization

Regional and country updates

African Region, Dr Jean Marie Trapsida (PL2-A)American Region, Dr Justina Molzon (PL2-B)European Region, Dr Nina Sautenkova (PL2-C)Eastern Mediterranean Region, Dr Zafir Mirza (PL2-D)Western Pacific Region, Dr Budiono Santoso (PL2-F)

Reflections on Eleventh ICDRA

Fernando de Andres, Spanish Agency for Medicines and Medical Devices,Spain

Spain's general objective in holding the Eleventh International Conferenceof Drug Regulatory Authorities was to continue with the idea of a forumwhere health oriented issues related to medicines could be discussed byofficials from regulatory authorities around the world. The conferencewas seen as important in being exclusively tailored to drug regulatoryauthorities, but with an open, pragmatic approach to consider inputand/or contributions from officials from developed and developing

Update on Eleventh ICDRA Recommendations and WHO Progress Report

1512th ICDRA Proceedings

countries. It was a great honour for Spain to convene the Eleventh ICDRA,which attracted over 240 participants from 113 countries.

The Eleventh ICDRA in particular targeted the promotion of collaborationbetween drug regulatory authorities, the importance of reaching aconsensus on issues of common interest and international relevance, andin facilitating timely and adequate exchange of information, not onlybetween regulatory authorities themselves but also with the participationof reliable reference organizations.

The conference focused on presentation and discussion of many importanttopics which have an impact on public health, including:

• Regulatory aspects of access to medicines• Strengthening of regulatory frameworks for medicinal products• Pharmacovigilance Practices• Pharmacopoeias in a changing regulatory environment• Regulatory assessment of combination products• Regulators, good clinical practice and ethics• Public health needs vs. the marketplace• Safety of herbal medicines• Assuring quality and safety of blood products• Human tissue: problems and challenges for regulators• Regulatory tools for providing drug information• Harmonization updates• Regulatory aspects of supply of quality medicines• Promoting good regulatory practices• Implications of regulatory decisions for pharmacoeconomics• Consequences of the TRIPS agreement• Impact of patents on access to medicines• Counterfeit medicines (pre-ICDRA meeting)• Reference comparator for generic medicines• Doping in sport

Some general issues were stressed during the conference. The mostimportant messages among these were:

• That regulation does not end with authorization to market andefficient pharmacovigilance should be in place and that the dataproduced should be shared by the different health systems.

• Counterfeit medicines are a growing problem with increasing impact.• Regulation is not a blind process; needed drugs should be identifiedand favoured. Availability is not the same as access: public health


regulators should therefore explore ways to facilitate access toneeded drugs.

• Even if efficient use of medicines is not always considered a part ofthe regulatory process, regulatory parties should at least ensure thatthere are sufficient data on which prescribers may base comparativetherapeutic alternatives so that an informed choice can be made.Evidence should be produced and always be available on file andshared by the different health systems.

Global progress report on recommendationsfrom the Eleventh International Conferenceof Drug Regulatory Authorities (ICDRA), Madrid, 2004

Dr Howard Zucker, World Health Organization

Progress has been made in many areas of medicines regulation as a resultof the International Conferences of Drug Regulatory Authorities. Asglobalization continues and has a profound impact on the developmentand marketing of medicines, strong international collaboration amongregulatory authorities is needed to safeguard public health interests.

In view of continued regulatory problems and new challenges, theimportance of government commitment to strengthening nationalregulatory systems and policies and the need to intensify internationalcollaboration to improve access to safe and effective medicines of goodquality is of major importance. The World Health Organization remainscommitted to serving regulatory authorities worldwide and has pleasure inpresenting an overview of the main activities which have taken placeworldwide with specific reference to recommendations made during theEleventh ICDRA held in Madrid in 2004.

Regulatory aspects of access to medicinesThe mission of regulatory authorities is to promote and protect publichealth. The lack of access to medicines remains a huge concern,whether these are essential medicines, vaccines, orphan drugs or drugsfor tropical diseases. To facilitate access, regulators and all otherstakeholders need to be actively involved in identifying difficulties andseeking solutions which will lead to balanced approaches which do notcompromise public health safeguards.

Recommendation Regulators have a role and responsibility to


facilitate access to drugs of public health importance includingproposing changes to the respective regulations in order to facilitateaccess without compromising quality, safety and efficacy.

Unfortunately, priority drugs of public health importance still do not getthe priority treatment they deserve. For example, some HIV medicinesdo not have national marketing authorization in many of the countrieswhere they are most needed. The time to licensing in some countriescan take up to two years to complete even if the product is alreadylicensed by well established regulatory authorities of developedcountries.

Recommendation When considering marketing authorization(registration) applications, regulators should give priority to medicinesof high public health importance in their countries. Regulators shouldconsider mechanisms to facilitate registration, such as reducing fees orother related costs.

In Collaboration with WHO, the European Union has introducedlegislation (Article 58) to provide scientific assessment and advice toWHO which may serve as an indicator of marketing suitability forproducts which are not marketed in the EU. This system offersauthorities with limited regulatory capacity the possibility of obtainingan assessment by a highly developed agency. The procedure will speedup the marketing process for priority medicines. This topic will bediscussed fully during the ICDRA session on Access to Medicines.

Pharmacovigilance PracticesSpontaneous reporting is the mechanism used for compiling adversedrug reaction reports and regulatory authorities take importantdecisions based on these data. Pharmacovigilance is a broad concept todescribe activities of safety monitoring, but also includes there-evaluation of marketed drugs, risk management, communicating druginformation, promoting rational drug use and crisis preparedness. It isbecoming increasingly important to provide training in all of theseactivity areas and to carry out intensive monitoring of new drugs inorder to evaluate the risk/benefit of medicines. Increasingly, medicinesare being used for off-label indications for specific public health needsand it is important that sufficient data is available to the nationalregulatory authority on safety, efficacy and quality.

Recommendation WHO should coordinate and develop training


resources in pharmacovigilance and pharmacoepidemiology and expand itscommitment to include training programmes for staff in each of itsregions

WHO has organized training courses on pharmacovigilance throughoutthe world. A training course in South Africa, for example, was held tointroduce the concept of pharmacovigilance and pharmacoepidemiologyinto HIV/AIDS programmes in Africa. Countries participating were:Kenya, Malawi, Mozambique, Nigeria, South Africa, Uganda, UnitedRepublic of Tanzania, Zambia. Outcomes of the training includednomination of a focal point to coordinate activities in the region, andstrategy development including spontaneous reporting in Uganda andZambia, cohort studies in Mozambique and Nigeria, or prescriptionevent monitoring in South Africa and Tanzania.

Recommendation WHO should provide, upon request, technical adviceand support to Member States on the appropriateness of post-marketing surveillance plans submitted by sponsors when a medicine isbeing introduced to manage a specific public health campaign in thatcountry.

WHO has responded to specific requests from countries on issuesconcerning the safety of medicines. Reports have been published on therisk-benefit of antimalarial drugs such as chlorproguanil/dapsone.Safety issues of amodiaquine/ artesunate are currently being analysedand will be reported later this year. A case-study has been conducted ofsafety issues concerning use of herbal products worldwide andspecifically the herbal remedy, kava.

Pharmacopoeias in a changing regulatory environmentPharmacopoeial standard-setting for starting materials and finisheddosage forms provides the means of ensuring the quality of medicines,particularly multisource (generic) products. Increased collaboration andcoordination at international level of pharmacopoeial bodies and allrelated parties is needed (i) for the development and analysis of qualitycontrol specifications; (ii) to speed up development of pharmacopoeialspecifications; (iii) to address the increasing diversity and complexity ofimpurity profiles and limits set at international level, especially forpharmaceutical starting materials; and (iv) to promote independent andworldwide validation of analytical methods to ensure the quality oftraded and sourced products internationally.


Recommendation In collaboration with those concerned, WHO shouldorganize an international conference on pharmacopoeial issues toexchange views and experiences among pharmacopoeial bodies andregulators. Negotiations are under way to launch the first forum ofpharmacopoeial commissions

WHO has approached Member States interested in organizing aconference where pharmacopoeial issues can be debated.

Recommendation In collaboration with parties concerned, WHO shoulddevelop a harmonized approach to providing internationally validatedspecifications for medicines for neglected and emerging diseases ofhigh public health risk.

WHO has developed 20 new international monographs, validated bynational quality control laboratories and WHO Collaborating Centres.The monographs cover HIV, tuberculosis and antimalarial medicines.Others, such as oseltamivir for influenza, are under development. Allmonographs are published on the WHO medicines website. They are ofparticular interest to quality control laboratories and manufacturerswishing to test the quality of products traded internationally or by UNprocurement agencies and the Prequalification Project.

Recommendation WHO should continue to support the establishmentof international chemical reference substances (ICRS) and assist in theirsupply, particularly for medicines used in the treatment of diseases ofhigh public health impact.

The WHO Collaborating Centre has established 11 new internationalchemical reference substances (ICRS) for antiretrovirals. The ICRS, usedtogether with monographs, are needed for quality control testing. ICRShave been supplied free of charge to a number of national qualitycontrol laboratories in developing countries.

Regulatory assessment of combination productsCombination products for various diseases have always been used inmedical practice. Today, HIV/AIDS, tuberculosis and malaria are themajor infectious diseases threatening public health and the focus ofmany national, regional and global initiatives. Combination therapy isconsidered essential for their treatment as well as for the prevention ofdrug resistance. Attempts to manage these diseases include thedevelopment of fixed dose combinations (FDC) of individual drugs to be


administered together in one finished dosage form. Well documentedclinical evidence of the efficacy and safety of the loose combination isa key entry point for development of any FDC medicine. In 2004, at thetime of the 11th ICDRA, there were no uniform principles, guidelines orinternational standards addressing the development and regulatoryassessment of FDCs. Only a few developed countries had specific FDCregulatory guidelines available and irrational combinations are stillfound in several markets. Progress is finally being made.

Recommendation WHO is urged to create - as a matter of urgencymodelguidelines for regulatory approval of prescription-only fixed dosecombination drugs with special emphasis on drugs for communicablediseases with high public health impact.

WHO Guidelines have now been developed and published using the bestknowledge available internationally in diseases of public health such asHIV, malaria and tuberculosis. The Guidelines serve as an important toolfor assessments made by the WHO prequalification project andfixed-dose combination medicines are now included in the list ofprequalified products. The WHO guidelines for registration of fixed dosecombination products are available from the WHO website athttp://www.who.int/medicines..

Regulators, good clinical practice and ethicsApplication of good clinical practice (GCP) guidelines assures thatclinical studies on medicinal products meet scientific and ethicalrequirements. However, recent advances in medicine may encompassareas of clinical research not covered by existing GCP guidelines andthis gap should be filled since all clinical research, including research ongene therapy and biotechnology products, should be conducted underrigorously implemented GCP. Since data on the safety and efficacy ofinnovative products may be limited, it is important that nationalregulatory authorities strengthen mechanisms to share knowledge andexperience. Given the increasing tendency to involve vulnerablesubjects in research, there is a special need to strengthen theapplication of ethical principles in research carried out in thesepopulations.

Recommendation WHO is requested to gather existing knowledge andexperience of safety, efficacy and quality of innovative biotechnologyproducts and share this information with Member States.


WHO receives requests from countries for advice on appropriateregulatory oversight for biological therapeutics. The number ofapproved innovative biotherapeutic products is expected to increasesubstantially over the coming years. In addition, the imminent patentexpiration of many biotechnology products will result in a substantialincrease in "follow-on" or "biosimiliar" products. WHO is also receivingrequests from countries for advice on appropriate regulatory oversightfor biological therapeutics, since the potential for success oftherapeutic biological products used in treatment of a wide variety ofchronic diseases is being tempered by concerns over quality, safety andavailability.

Experience reported from one regulatory authority showed thatinappropriate quality determinations can lead to life threateningclinical problems, and adverse drug reactions could occur with a varietyof products. The potential for substandard and counterfeit biotechproducts represents an important matter of concern.

WHO initiatives also include a WHO working group on gene therapies,updating of existing WHO written standards, the establishment of newWHO written standards to promote and develop appropriateunderstanding of risks and benefits from biotechnological products,continued development of new reference materials and strengtheningof regulatory technical capacity.

WHO will also develop consensus on the global needs, priorities andpotential role for global standardization of biotherapeutics for themajor chronic diseases and also collate information on substandard orcounterfeit biological medicines for chronic diseases. The issue ofbiosimiliar biologics was discussed in a meeting prior to the ICDRA heldon 1-2 April 2006.

Recommendation WHO is requested to accelerate its work inregulatory capacity building for assessment of vaccines and medicinesof public health importance and to explore options for providingexternal regulatory expert support for assessment of clinical trialapplications in countries with limited resources.

The Developing Country Vaccine Regulators Network is rapidly becominga key forum for regulators. At the global level the Network has rapidlybecome a key forum for regulators of developing countries where issuesrelevant to the clinical evaluation of new vaccines can be discussed in afrank and constructive way. Topics addressed in 2005 included new TB


vaccines, HIV Vaccines, rotavirus vaccines and human papilloma virusvaccines. The opportunity to meet with vaccine developers, trialsponsors, WHO experts and regulatory colleagues, has increasedawareness of regulatory perspectives regarding development andregistration of new vaccines. At the regional level, regulators fromAfrican countries have participated in several activities planned tostrengthen capacity for evaluation of vaccines during clinicaldevelopment and for registration. These activities provide essentialfeedback from users of WHO norms and standards.

WHO tools available for capacity building include the Handbook for goodclinical research practice (GCP); and Safety monitoring of medicines:pharmacovigilance as an essential tool for public health.

Public health needs vs. the marketplaceDevelopment of new drugs is often driven by market forces. Somemedicines for priority disease of public health impact are commerciallyunattractive, and this is often because they are unaffordable by poorpopulations. Effective mechanisms compensating for this market failureare needed to bridge the gap. Regulators, together with otherstakeholders, can play an important role in supporting initiatives aimedat creating new drugs for diseases where there is no marketattractiveness by motivating investment into research anddevelopment. However, there is also a regulatory capacity gap toovercome, as regulators from developing countries have previously hadlimited capacity to advise on drug development or assess the safety,efficacy and quality of new drugs created for diseases exclusivelyprevalent in those settings.

Recommendation WHO is encouraged to continue cooperation withMember States, industry and other stakeholders in order to promoteand facilitate development of new treatments for diseases that havelittle market potential, in particular for diseases prevalent indeveloping countries (neglected diseases). Mechanisms and incentivesshould be created for more proactive involvement of nationalregulatory authorities in all stages of research and development ofthese products.

WHO programmes are collaborating to provide new treatments fordiseases of public health importance. Examples of treatments underdevelopment include clinical trials to shorten treatment regimens fortuberculosis. Trials have been conducted by the South African Medical


Research Council in collaboration with WHO. Other initiatives involvediseases such as leishmaniasis, African trypanosomiasis, and schistosomiasis.

Recommendation WHO should continue facilitating regulatorycapacity building and networking among regulators of differentcountries in order to empower regulators in countries with limitedresources to take informed and evidence-based decisions.

WHO has provided numerous training workshops for regulators indifferent regions and countries. These are either more general ordisease or product specific (in the case of training organized by thePrequalification Programme). WHO has involved regulators from manycountries in its Prequalification Programme which facilitates capacitybuilding and networking.

WHO activities in capacity building also cover provision of informationand tools needed to attain regulatory objectives. The WHO Medicineswebsite contains the information necessary to assist regulatoryauthorities.

Safety of herbal medicinesThe use of herbal medicines is increasing rapidly worldwide. Althoughthe reasons for this may vary in different settings, the safety of herbalmedicines is a common global concern. Both public and national healthauthorities are committed to making progress in ensuring the safe useof herbal medicines. This is a very complicated and complex issuebecause of differing regulatory requirements, availability and suitabilityof technical methods for quality control, post-marketing qualitysurveillance, and safety monitoring, the presence or absence ofqualified practitioners and consumer education. Major issues concerningthe safe use of herbal medicines are being addressed by WHO.

Recommendation The safe use of herbal medicines requires adequateregulation. Member States should continue to adapt their nationaland/or regional regulatory framework, including pharmacovigilance,to the specific requirements of herbal medicines. WHO should continueto provide support including guidance and training programmes.

WHO has conducted a global survey on progress of countries to regulatetheir markets and a document entitled National policy on traditionalmedicine and regulation of herbal medicines: Report of a WHO globalsurvey was published in June 2005.


WHO guidelines for evidence-based traditional medicine are underdevelopment. Safety monitoring of herbal medicines guidelines havebeen published and are also being translated into Spanish and Chinese.In addition, a WHO interregional training workshop on safety monitoringfor herbal medicines will take place in December 2006 and 2008.

Recommendation Quality assurance and quality control of herbalmedicines presents specific challenges. WHO should continue to providetechnical guidelines, particularly for the quality control of combinationproducts and criteria for reference substances and materials.

The following WHO technical guidelines have been published:

•WHO guidelines on assessing quality and safety of herbal medicineswith reference to contaminants and residues.

•WHO GACP monograph for Artemisia Annua L.•WHO draft guidelines for the selection of substances for qualitycontrol of herbal medicines (outline and key technical issues discussedat two WHO working group meetings in 2004 and 2005).

•WHO GMP: Updated supplementary guidelines for manufacture ofherbal medicines.

• Quality control methods for medicinal plant materials.• Support to national capacity building on quality control of herbalmedicines.

•WHO Interregional Training Workshop on GACP and GMP for HerbalMedicines, held in China, September 2005.

Recommendation Awareness among consumers on the benefits andlimitations of herbal medicines needs to be strengthened. MemberStates should consider preparing a policy on consumer information andguidelines on the advertising of herbal medicines. WHO should providegeneral guidance to support these activities.

Three WHO linked activities - guidelines, capacity building and trainingworkshops have been carried out. In particular, the WHO guideline fordevelopment of consumer Information for proper use of traditional andcomplementary/alternative medicine is now being translated intoChinese, French and Spanish. An interregional training workshop onconsumer education is scheduled for 2007.

Recommendation Providers of traditional/complementary health careplay an important role in the safe use of herbal medicines. Member


States should explore appropriate mechanisms to ensure adequatetraining and education of these health care providers. WHO shouldprovide policy and technical guidance. WHO policy and technical guidance

WHO guidelines on basic training and safety in phytotherapy will befinalized in 2006. The guidelines include three different trainingprogrammes for prescribers, dispensers, and distributors. Popular usesof phytotherapy in traditional Chinese medicine, Ayurvedic medicine,Unani medicine and naturopathy are described.

Recommendation Regulatory agencies should work together to makethe best use of scientific resources related to herbal medicines. Sharingnational experience and information is crucial. WHO should facilitatethese activities e.g. by providing updated monographs on medicinalplants and technical/regulatory guidance.

WHO monographs on selected medicinal plants, with 28 monographshave been published and WHO monographs on selected medicinal plantscommonly used in the Newly Independent States (NIS) will be finalizedin July 2006.

A WHO network of regulatory authorities, the International RegulatoryCooperation of Herbal Medicines (IRCH), with an initial invitation to 16national drug authorities, will be launched in 2006 and the second WHOworking group meeting on the subject is scheduled in October 2006.

Assuring quality and safety of blood productsBlood and blood products are essential for the treatment of a number oflife-threatening conditions. However, because blood may transmitinfectious agents this can also cause severe harm to the recipients.During the Ninth and Tenth ICDRAs, emphasis was therefore given toprocedures aimed at inactivating and removing infectious agents. Inorder to avoid transmission of infectious agents in a reliable manner,good manufacturing practice (GMP) has to be implemented as anessential tool of quality assurance. In addition, adherence to GMP at alllevels of the process, from donor to recipient, is a prerequisite forconsistent quality in the preparation of blood and blood products.

Recommendation WHO's policy to give high priority to theimplementation of GMP in blood and plasma collection establishmentsis welcomed. Educational programmes and training opportunitiesshould be continued and strengthened. Guidance documents should be


developed and/or updated.

Adherence to good manufacturing practice (GMP) at all levels of theprocess, from donor to recipient, is a prerequisite for consistent qualityand safety in the preparation of blood and blood products and anessential tool of quality assurance.

To support the correct implementation of GMP and quality assurancetools, training workshops were organized during 2004-5 in threedifferent Regions by WHO and include a workshop on Harmonization ofQuality assurance systems for blood products in Asian countries, aworkshop on GMP for blood and plasma collection establishments, and aworkshop on Quality assurance and safety of plasma and plasmaderivatives. The workshops developed comprehensive guidance forregulatory authorities, national blood programmes and localmanufacturers of participating countries. Between 10 and 13 countriesper region participated. WHO considers this activity essential tostrengthening the safety of blood products at global level and effortswill continue in this direction.

Recommendation WHO should contribute to advancing the technicalexpertise of regulatory authorities by enabling the creation of regionalnetworks to facilitate their regulatory role in the area of blood andblood products.

In order to support networks, WHO Recommendations and Guidelineshave been developed. These are internationally agreed documents,widely consulted with national regulatory authorities, manufacturersand representatives of blood establishments and includeRecommendations for the production, control and regulation of humanplasma for fractionation, which concern the quality criteria of plasmafor fractionation and WHO Guidelines on tissue infectivity distribution intransmissible spongiform encephalopathies which define preventivemeasures needed to minimize risk to humans from both animal andhuman derived materials involved in the preparation of medicinalproducts as well as the major categories of TSE infectivity, both inhuman and animal tissues.

Recommendation WHO should facilitate the formation of a globalnetwork of regulatory authorities for blood and blood products.

A blood regulators network is being formed and WHO is fostering


development of an international consensus on effective regulatoryapproaches. Information on these activities and WHO Recommen-dations, Guidelines and international biological reference materialssupporting the regulation and control of blood products can be found onthe WHO website.

Human tissue: problems and challenges for regulatorsThe transplantation of human cells, tissues and organs has become thetreatment of choice for a wide range of both fatal and non-fataldiseases. The volume and complexity of activities relating totransplantation is growing rapidly. The ethical and safety risks oftransplantation require effective regulatory oversight at national leveland international cooperation.

Recommendation To facilitate this process, WHO is requested todevelop clear guidelines for the quality, safety and efficacy of humancell, tissue and organ transplantation.

WHO has convened the First Global Consultation on regulatoryrequirements for human cells and tissues for transplantation. Adocument has been submitted to public enquiry, and the consultationprocess will be adopted during the Second Global Consultation in June2006. This activity is complemented by development of Key safetyrequirements for essential minimally processed human cells and tissuesfor transplantation.

Ongoing regional consultations of health authorities in charge of cell,tissue and organ transplantation will lead to submission of updatedGuiding Principles on Transplantation to the WHO Executive Board inJanuary 2007.

Recommendations To complement the regulation of human cell, tissueand organ transplantation, Member States should develop andimplement effective surveillance after cell, tissue and organtransplantation.

WHO should facilitate these surveillance activities by development ofappropriate written standards and reference materials.

Regional consultations of health authorities in charge of cell, tissue andorgan transplantation aim at creating a global network to be used interalia for surveillance and vigilance of safety risks. WHO is also a partner


in a project to define terminology and classification of adverse eventsand reactions. The Global Knowledge Base on Transplantation (GKT) willinclude surveillance and vigilance of safety risks in cell tissues andorgan transplantation.

Regulatory tools for providing drug informationAccurate drug information is essential for the rational use of medicines.Assessment of safety, efficacy and quality of products includes alsoassessment of product information provided by the applicant of themarketing authorization. Although national regulatory authorities havethe responsibility of validating the correctness and appropriateness ofthe product information, resource constraints may limit the capacity ofsmall regulatory authorities to be able to verify the quality ofinformation provided by the manufacturers.

Recommendation WHO should develop guidance and new tools tocontrol promotion and drug information.

WHO has organized a study to assess industry promotion techniques,such as providing information on a specific disease of health conditionand then directing readers to their product as the solution. The resultsof the study are expected later in 2006.

WHO has organized training and workshops to establish regionalreference drug information. Drug information which a manufacturer/producer generates to support evaluation and marketing of themedicinal product, (know also as the summary of productcharacteristics) can vary from country to country. The same applies tothe multisource generic products meaning that the same product fromdifferent manufacturers can have very different product information.WHO is promoting use of a harmonized reference model for use inseveral countries in order to improve interchangeability and clarity ofinformation.

Promoting good regulatory practicesTo meet the objectives of promoting and protecting public health,national regulatory authorities need to carry out their functionseffectively and efficiently within a set of principles based ontransparency and good governance. The issues that are necessary topromote good regulatory practices nationally and internationallyinclude sustainability of resources, optimal structure, effectivecooperation within the agency and with other agencies, transparency


and accountability, competence in evaluating efficacy, safety, andquality, timeliness, independence, collaboration as a service provider,sharing information, harmonization, and mutual recognition. In manycases, regulatory authorities do not have sufficient resources to carryout these activities. Most importantly, regulatory agencies must beaccountable and decision-making processes must be transparent.However, this needs to be balanced against the need for protecting theconfidentiality of the data that has been submitted by themanufacturer. Sources of information and the decision process shouldbe made publicly available whenever possible.

Good regulatory practices thus cover an evolutionary process, with goodpractices built into the systems which continuously reinforcecollaboration and trust. Regulatory authorities should establishmechanisms to ensure the quality of the procedures they operate to.

Recommendation WHO should develop the tools and guidelinesneeded to help national regulatory authorities effectively implementthe principles of good regulatory practices.

WHO should promote and provide technical assistance for theevaluation of regulatory capacity of national regulatory authorities inorder to analyse the situation and to undertake necessary correctivemeasures.

WHO has developed a comprehensive data collection tool forassessment of medicines regulatory systems. Assessments of regulatorycapacity were carried out in several countries - Tanzania, Ethiopia,Mali, Senegal, Ghana, Malawi, Zambia and South Africa - with actionplans developed and finalized with technical support from WHO. Theassessment tool has also been promoted in several other countries withtechnical assistance from WHO

Intercountry training on product registration with emphasis onantiretroviral drugs was organized for regulators in Africa. Acomputerized software for regulators, SIAMED, has been installed andtraining provided to several regulators in African countries. Technicaland financial support has been provided to regulators in countries ofthe Greater Mekong Region to combat counterfeit drugs

Regulatory aspects of supply of quality medicinesAccess to quality medicines contributes to improving human health andpromoting well-being. Rigorous implementation of good manufacturing


practices in the production of medicines will ensure that only safe,quality products are allowed on the market.

The promotion of good quality pharmaceutical products, and thedevelopment of quality control methods - in particular to detectcounterfeit drugs - is important for public health. Participants agreedon the need for international harmonization of quality control methods,and recognized WHO s leadership role in providing normative guidance�

for quality control and quality assurance of medicines,

Special efforts have been undertaken to raise awareness of theimportance of regulatory measures covering trade in products andstarting materials, including active pharmaceutical ingredients andexcipients, and implementation of good manufacturing practices.

Recommendation WHO should continue the Pre-qualification Project ofmedicines for priority disease programmes, particularly HIV, malaria andtuberculosis.

The Pre-qualification Project has now extended beyond products andincludes quality control laboratories. In 2005, about 350 assessmentreports were submitted and 52 inspections made of manufacturers offinished dosage forms and active pharmaceutical ingredients as well asorganizations conducting bioequivalence studies. Twenty-two newantiretroviral products and one antimalarial product were added to thelist of prequalified products

Recommendation WHO should foster collaboration betweenmanufacturers and regulators in the implementation of GMP and providetraining.

WHO has organized the following workshops:

GMP and Quality assurance of antimalarial medicines withemphasis on Prequalification of Artemisinin-based combinationproducts (ACTs), held in Bangkok, Thailand; GMP and QualityAssurance of TB products including Bioequivalence issues, KualaLumpur , Malaysia; GMP and Quality Assurance of HIV productsincluding Bioequivalence issues, Shanghai, China; Training in GoodManufacturing Practices for inspectors from the MedicinesRegulatory Authority in South Africa; for inspectors from the StateDrug Administration (SFDA), Food and Drug Administration of theJiangsu Province and Zhejiang Province, Peoples Republic of China;


Training Workshop On Pharmaceutical Quality, Good ManufacturingPractice & Bioequivalence Kiev, Ukraine; Training Workshop onPharmaceutical Quality, Good Manufacturing Practice andBioequivalence with a Focus on Artemisinin containing antimalarialmedicines, China; and a Training Workshop on PharmaceuticalQuality and Bioequivalence, Hanoi, Vietnam, 17-19 January 2006

Recommendation WHO should continue to develop internationalguidelines for registration of multisource (generic) products.

WHO has continued its efforts to update the guidelines for registrationof multisource (generic) products. Four new or updated guidelines onhow to establish interchangeability (bioequivalence) of genericmedicines have been completed WHO has also produced three newGMP supplementary texts and three new guidance texts in the area ofbioequivalence of multisource medicines.

Current topicsThe current topics session provides an opportunity for regulators toexpress their views on newly-emerging topics which have not beenreflected in the conference programme. Often, the topics raised in thissession lead to substantial discussion during subsequent ICDRAs. This hasbeen the case in relation to counterfeit medicines and WHO has hadpositive responses from Member States and other partners in carryingout the following recommendation.

Recommendation WHO, in collaboration with other stakeholders,should develop a draft concept paper for an international convention oncounterfeit drugs. WHO should convene a meeting of nationalregulatory authorities to discuss further the concept paper and relatedissues before the next ICDRA.

A conference was organized in Rome in February 2006 and participantsagreed on the Declaration of Rome. In collaboration with the manystakeholders concerned with combating counterfeit medicines, WHO hasactively sought consensus on the feasibility of an internationalconvention. During a meeting organized in Rome, participants madeprogress in mapping out the foundations of an agreement on the workwhich need to be undertaken. As a first step, the Declaration of Romehelped establish IMPACT, a task force with the Secretariat based inWHO.


Regional and country updates

African RegionImplementation of 11

thICDRA recommendations in the African Region

encompasses activities undertaken by the Essential Medicines andTraditional Medicine Programmes as follows:

Improve access to medicines by registration of medicines of public healthimportance and use of full flexibility of the TRIPS Agreements:

A Regional workshop was organized on "Patents and access tomedicines: appropriate national and regional response" and countries- Cameroon, Ghana, Kenya, Nigeria, Tanzania and Uganda - startedreviewing their Patent Laws and Regulations;

Strengthening drug regulatory capacity:An assessment of Ghana, Kenya, Malawi, Nigeria and Zambia drugregulatory authorites was undertaken followed by development of thepaper on Drug regulatory authorities: current status and way forward;

Development of Regional Strategic Framework for strengthening DRAswas undertaken during the African Medicines Regulators Conferenceheld in Addis Ababa in 2005 and training of Regulators from 15countries in use of the WHO tool for assessing Medicine Regulatorysystems.

Quality and safetyTo intensify efforts in combating counterfeit medicines, anassessment of quality of medicines was undertaken in Nigeria. Thequality of antiretroviral samples was tested in selected countriesand a Sub regional Consultation and workshop on strengtheningquality control of antiretrovirals were held. Regulators from Ghana,Kenya, Nigeria, Sierra Leone, South Africa, Tanzania and Ugandaattended the International Conference on Counterfeit Drugs in Romain 2006.

Traditional medicineGuidelines for evaluation of the safety, efficacy and quality oftraditional medicines have been developed for registration purposesand professionals trained. Sub regional Harmonization initiatives areongoing in Eastern, Southern, Central and West Africa.


American Region

The Pan-American Network for Drug Regulatory HarmonizationIn 1999, Member States of the World Health Organization's Region of theAmericas (AMR) established, a regional initiative called the Pan AmericanNetwork for Drug Regulatory Harmonization (PANDRH). This represents astrategic effort by regulatory authorities to improve the quality, safetyand efficacy of the pharmaceutical market within the Region. It issupported by Resolution 42 of the PAHO/WHO Directing Council.

PANDRH encompasses work on regulatory harmonization carried out by thefive sub-regional free trade integration groups: the North American FreeTrade Agreement "NAFTA", the Central American Integration Agency"SICA", the Andean Community of Nations "CAN", the CaribbeanCommunity and Common Market "CARICOM", and the Southern ConeCommon Market "MERCOSUR". It is also a member of the GlobalCooperation Group of the International Conference of Harmonization(ICH), along with four other regional initiatives.

The fundamental strategy of PANDRH is cooperation among countriesthrough national regulatory authorities. Other key partners are the drugmanufacturing sectors, academia, nongovernmental organizations andSub-regional Economic Integration Blocks. A PANDRH objective is also toaddress Millenium Development Goal number 8: Development of globalpartnerships… "In cooperation with pharmaceutical companies, provideaccess to affordable, essential drugs in developing countries."

PANDRH has four components: The Pan American Conference, the SteeringCommittee, working groups and Secretariat. Operational guidelines,norms and regulation are developed by working groups, whose majoritymembers are experts from national regulatory agencies. PANDRH has 12working groups in different areas in drug harmonization: goodmanufacturing practices, bioequivalence, registration requirements, goodclinical practices, drug counterfeiting, drug classification, drugpromotion, good laboratory practices which includes the External QualityControl Program, vaccines, medicinal plants, and pharmacovigilance.

To date, PANDRH has adopted six regional technical documents includingthe Guideline for GMP inspection and Good Clinical Practices. Fivedocuments are currently posted in the web for public opinion, and 14more are being discussed by the working groups.


East Mediterranean RegionWHO's East Mediterranean Region (EMR) is composed of 22 countries.Although the majority are Arabic speaking, it is a very diverse region withbig countries like Pakistan, Iran and Afghanistan and six low-incomecountries, out of which 5 are in a chronic emergency state.

From the early 1980s, countries in the region have been active in ICDRA. Acomplementary regional forum was created in the early nineties’ the EastMediterranean Drug Regulatory Authorities Conference (EMDRAC) and fiveevents have been conducted. The aims of EMDRAC are to enhancecooperation between regulatory authorities in the region; identify andplan capacity building activities; and organize regional input to the ICDRA.Reactivation of EMDRAC is now being planned. Modalities were discussedduring this ICDRA with regulators from the Region. An active network ofregulators will soon be established and a first meeting will be held nextyear.

With reference to recommendations from the 11th ICDRA, regulators fullyappreciate their responsibility in accelerating access to medicines and asa result some countries in the region have adopted fast-track registrationmechanisms; In particular, TRIPS-plus provisions of Free Trade Agreementsare also a challenge in access to new medicines. Autonomous regulatoryauthorities now exist or are in making in around half the countries and 13out of 22 countries have agency websites.

Pharmacovigilance still remains an underdeveloped area andpharmacoeconomics and drug utilization studies are just beginning to beintroduced in a few countries. The; international pharmacopoeia has beentranslated into Arabic, and many regional experts serve on WHO globalexpert committees for medicines. The majority of countries have adoptedgood clinical practice guidelines following appropriate modification andadaptation. In addition, many of the countries in the region have nowadopted a regulatory framework for herbal medicines, and regionalguidelines on minimum requirements for registration of herbal medicineshave been developed.

Regional guidelines for development of national polices on traditionalmedicine and complementary alternative medicine are being finalizedafter a regional consultation, and a regional expert committee ontraditional medicine is being established to further promote and assistregulatory frameworks. A Regional Workshop on quality assurance andsafety of plasma and plasma derivatives was convened last year. Most of


the regulatory agencies have established basic requirements for productinformation, new medicine information centres are being set-up in somecountries of the region and three countries are being assessed for theirregulatory structures, functions and outcomes. With regard to theproblem of counterfeit medicines, which is increasing in a few countries,regulatory interventions are being planned in line with the ICDRArecommendations and recently launched IMPACT initiative. Eight nationalmedicine price surveys have been conducted.

European RegionNew European Union (EU) legislation entered into force in November2005, just after 10 new members joined the EU. The new legislation has aspecific article 58 ( the "WHO article") which allows for an EMEA scientificopinion for products that will be marketed outside of the EU; this is meantfor countries with limited regulatory authority capacity or expertise thatneed medicines that are normally not marketed in EU countries.

In terms of access to medicines, this legislation contains a fast trackprocedure for medicines of urgent public health need; it harmonizes andextends data protection by potentially one year, and it also containsseveral articles to streamline the registration procedures.

The WHO Priority Medicines Report has been published and referred toregulatory obstacles to drug development - and thus access - and gavesuggestions for addressing those barriers.

The network of drug regulatory authorities in the newly independentstates (NIS) continues to meet at least once a year, and collaboratesthrough exchange of information and training of staff. Technicalassistance has been provided to the Inspectorate in Ukraine within theframework of the WHO prequalification project, and to the Russianauthorities for quality assurance of TB and HIV medicines.

Authorities in the South Eastern European countries agreed on the need tocooperate more closely and proposed to establish a regional Council onMedicines.

Together with the Council of Europe, a multisectoral conference wasorganized in 2005 on counterfeit medicines which put forward a series ofrecommendations on how to better control the market and preventcounterfeits from entering the region.


South-East Asia RegionProgress in implementing the 11

thICDRA recommendations was the result

of planned activities although public recognition of activities provided anadded stimulus for action. Collaboration between regulatory authorities inthe region was encouraged by the WHO South-East Asia Regional Office(SEARO). In particular, the provision of independent unbiased informationsuch National Formularies on CD, helped the less-resourced agencies tomake better decisions on registration. In good clinical practice, Indiamade significant advances by developing a manual and holding a workshopto train and create awareness in sponsors as well as investigators. Thegrowth of contract research organizations in India was partly a stimulus tothis activity.

In traditional medicines, a regional workshop in the Democratic People’sRepublic of Korea provided an opportunity for Ministry of Health officialsto discuss common problems and share experiences in the regulation oftraditional medicines. The issue of quality and safety of blood productswas dealt with mainly by Thailand and an upcoming national meeting isplanned to develop a “road map” for the future. The project on“Transparency and Ethics in Drug Regulation” - a bi-regional activity withthe WHO Western Pacific Regional Office - provided a very goodopportunity for Thailand to evaluate its procedures and develop morerobust standard operating procedures as well as guidelines in theregulatory system. Indonesia is a newcomer to the project and it isanticipated that results will be seen in 2007.

Both Bangladesh and Sri Lanka promulgated national drug policies in whichdrug regulatory authorities had a central role. Cost-effectiveness wasrecommended as a criterion for drug registration in the Sri Lankan policy.In Pharmacovigilance, Bhutan developed their own national system andnow has a functioning website which provides information to itsprescribers. Disappointingly, some of the larger countries have yet toprogress on pharmacovigilance despite activities and plans of action fromquite some time ago. Avian influenza focused on use of oseltamivir and ameeting held in early 2006 provided and opportunity for regulators,Ministry of Health officials and manufactures to discuss matters of mutualinterest.

Counterfeit medicines continued to be a persisting problem; SEAROcooperation in the Rapid Alert System allowed greater overview ofproblems in Asia overall. Access continued to remain an issue in the regionand although regulation was recommended as a tool for improvement,


plans of action have yet to be implemented.

In conclusion, there has been significant progress in drug regulation, someof which can be attributed to the ICDRA recommendations. But muchmore can be achieved if there is greater political and administrative willwith adequate additional resources.

Western Pacific RegionThe report on the implementation of 11th ICDRA recommendations in theWestern Pacific Region covers activities undertaken by the WPRPharmaceutical programme, Traditional Medicines programme, and BloodSafety and Health Technologies. Various activities have been implementedin the pharmaceutical area which cover access and pharmaceuticalpolicies, good regulatory practices and access to medicines, medicinesregulation, evaluation and legislation, supply of quality medicines,combating counterfeit medicines, and rational use.

Technical support for member countries have been provided in theseareas. For improving access, WPRO has developed a Regional Strategy forImproving Access to Essential Medicines in the Western Pacific region,2005-2010, which serves as a guide for WHO and member countries. Tointensify efforts in combating counterfeit drugs, a Rapid Alert System forcombating counterfeit drugs has been initiated and implemented involving28 countries and partner organizations. In the area of traditionalmedicines, the Forum on Harmonization of Herbal Medicines (FHH) is oneof the major activities. Training has been conducted on the qualitymanagement of plasma collection and fractionation, and evaluation ofhepatitis B vaccine.

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